Effects of astemizole on ventricular activation, effective refractory periods, RT intervals, and programmed stimulation-induced ventricular arrhythmias in dog hearts with myocardial infarction.
To clarify the mechanisms of enhanced cardiotoxic effects of astemizole in ischemic hearts, we examined the effects of astemizole on ventricular activation, effective refractory periods (ERPs), RT intervals, and incidence of programmed electrical stimulation (PES)-induced ventricular arrhythmias in the dog heart after myocardial infarction. Myocardial infarction was produced by the two-stage ligation of left anterior descending coronary artery in dogs. At 7 days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and the normal zones for applying an electrical stimulation or recording the ventricular activation. Ventricular-activation delay was measured in a premature excitation, which was produced by a stimulation at a coupling interval between 300 and 140 ms on the ventricular surface of the normal zone. The ERP and the RT interval were determined during atrial pacing. The ventricular-activation delay increased after astemizole at doses of 0.3-3 mg/kg in the infarcted zone and at 3 mg/kg in the normal zone. Astemizole at doses of 0.3-3 mg/kg significantly prolonged the ERP to a greater extent in the infarcted zone than in the normal zone, and thus a dispersion of ERP between normal and infarcted zones increased. The RT interval in the normal zone significantly increased after astemizole to a greater extent at a long coupling interval. The RT interval in the infarcted zone also increased after astemizole at doses of 0.1-3 mg/kg to a greater extent than that in the normal zone. Astemizole at doses of 0.3-3 mg/kg increased the incidence of PES-induced ventricular arrhythmias. In conclusion, enhanced cardiotoxic effects of astemizole in ischemic hearts may be caused by increased activation delay in the ischemic regions and increased ERP dispersion in the ventricle.
Hashimoto
H
H
Hospital Pharmacy, Hamamatsu University School of Medicine, Japan.
Nishimoto
M
M
Ohmura
T
T
Watanabe
S
S
Ikeda
Y
Y
Nakamura
R
R
Umemura
K
K
Nakashima
M
M
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000503:physiopathology; D016589:Astemizole / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000503:physiopathology; D016276:Ventricular Function / Q000187:drug effects*
D006634:Histamine H1 Antagonists; D016589:Astemizole